Comparative Efficacy of Ticagrelor Versus Aspirin on Blood Viscosity in Peripheral Artery Disease Patients With Type 2 Diabetes

Comparative Efficacy of Ticagrelor Versus Aspirin on Blood Viscosity in Peripheral Artery Disease (PAD) Patients With Type 2 Diabetes (T2D)

The hypothesis being that both aspirin-ticagrelor and ticagrelor monotherapy will be superior to aspirin monotherapy in the reduction of whole blood viscosity at the end of each 4 week treatment period. Study participants will be randomized into 3 groups, and each group will receive each of 3 treatments in the cross-over study. At the end of each individual 4 week treatment period the investigators will determine whether there are differences in low and high shear rate dependent viscosity and investigate the effect of the treatment on peripheral arterial blood flow using pulse volume recordings, ankle brachial index and toe pressures. Subjects will be eligible if they have ankle-brachial index less than or equal to 0.85, or if a patient's blood vessels are calcified, patients will have toe-brachial index less than or equal to 0.6 performed using continuous-wave Doppler.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes; Peripheral Artery Disease
• Intervention / Treatment: Drug: Aspirin; Drug: Ticagrelor Placebo; Drug: Ticagrelor; Drug: Aspirin Placebo

Detailed Description

Ticagrelor has been shown to significantly reduce the rate of cardiovascular disease (CVD) events and death compared with clopidogrel in patients having prior acute coronary syndrome. A number of outcome studies have demonstrated the risk of major CVD events increased with blood viscosity. Stroke patients and those with stroke risk factors were shown to have chronically elevated blood viscosity relative to healthy controls. Based on prior observations, the rationale for this study is to demonstrate that both aspirin-ticagrelor and ticagrelor monotherapy will be superior to aspirin monotherapy in the reduction of whole blood viscosity at the end of each 4 week treatment period.

The primary objectives for this study is to: (1) Compare the effect of aspirin-ticagrelor with aspirin in a double blind, randomized, cross-over study design (weeks 1-4, weeks 6-10, and weeks 12-16) on blood viscosity at both low (5 s-¹) and high (300 s-¹) shear rates at the end of each 4-week treatment period; and (2) to compare the effect of ticagrelor mono-therapy with aspirin in a double blind, randomized, cross-over study design (weeks 1-4, weeks 6-10, and weeks 12-16) on blood viscosity at both low (5 s-¹) and high (300 s-¹) at the end of each 4-week treatment.

The secondary objectives for this study include: (1) a determination as to whether there are differences in low and high shear rate dependent viscosity with treatment by ticagrelor alone and combination aspirin-ticagrelor. Additionally, investigated will be the effect of the treatment on peripheral arterial blood flow using pulse volume recordings, ankle brachial index, and toe pressures.

The general approach to evaluation of drug efficacy will be through blood samples collected with a standard venipuncture for viscosity testing. Blood viscosity will be measured using an automated scanning capillary tube viscometer across a physiologic range of shear rates of 1-1000 s-1 in increments of 0.1 s-1. Blood viscosity levels at 5 s-1 will be reported as low-shear viscosity, and blood viscosity measurements at 300 s-1 will be reported as high-shear viscosity. Additionally, pulse volume recordings will be simultaneously obtained at the level of the ankle, metatarsal and toe bilaterally according to standard protocol, and Continuous-wave Doppler will be used to determine ankle-brachial indices or toe-brachial indices, and flow velocity profiles.

• Study Type: Interventional
• Enrollment (Actual): 70
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Female or male aged ≥ 35 years
• Type 2 diabetes mellitus
• Symptomatic PAD
• Ankle-brachial index ≤ 0.85 or calcified blood vessels with toe-brachial index ≤ 0.6 and/or abnormal post-exercise ankle-brachial index
• Prior surgical or percutaneous intervention of the peripheral arteries ≥12 months previously with a residual stenoses of ≥50% in a non-dilated artery.

Exclusion Criteria:

• Subject is pregnant or breast-feeding
• Planned revascularization or amputation
• Known bleeding disorder
• History of intracranial hemorrhag3
• Considered at risk of hemorrhagic events
• Hypersensitivity or allergic reactions to aspirin
• Concomitant use of anticoagulants such as warfarin, dabigatran, factor Xa inhibitors or antiplatelet drugs such as clopidogrel, dipyridamole and sulfapyridine
• Subject has a condition or circumstance which would prevent them from adhering to treatment regimens
• Subject has active infection
• Subject has an anemia
• Subject has given blood or received a blood transfusion at any point during the study
• Subject has polycythemia vera or any hyperviscosity syndrome
• Subjects with Waldenstrom's macroglobulinemia who have an increased risk of hyperviscosity syndrome
• Subject has history of severe liver disease, obstructive liver disease such as primary biliary cirrhosis or end-stage renal disease (eGFR <30 mL/min/m2)
• Family members or employees of the investigator or study centers involved in the study
• Subject has poor diabetes or hypertension control (systolic blood pressure ≥ 180 mmHg or diastolic blood pressure ≥ 100 mmHg)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Aspirin/Ticagrelor placebo; aspirin 81 mg daily and ticagrelor placebo twice daily	Drug: Aspirin; Aspirin 81mg; Other Names: ASA; Drug: Ticagrelor Placebo; Other Names: Placebo
Active Comparator: Aspirin/Ticagrelor; aspirin 81 mg daily and ticagrelor 90 mg twice daily	Drug: Aspirin; Aspirin 81mg; Other Names: ASA; Drug: Ticagrelor; ticagrelor 90 mg
Active Comparator: Aspirin Placebo/Ticagrelor; aspirin placebo daily and ticagrelor 90 mg twice daily	Drug: Ticagrelor; ticagrelor 90 mg; Drug: Aspirin Placebo; Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change in Low Shear Blood Viscosity	Compare the effect of aspirin-ticagrelor and ticagrelor monotherapy with aspirin on blood viscosity from week 16 to baseline	baseline, week 16
Mean Change in High Shear Blood Viscosity	Compare the effect of aspirin-ticagrelor and ticagrelor monotherapy with aspirin on blood viscosity at week 16 to baseline	baseline and week 16

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change in Peripheral Arterial Blood Flow	Measure of treatment effect using pulse volume recordings of the ankle, great toe and brachial artery to calculate the ankle brachial index (ABI) and toe brachial index (TBI) at week 16 compared to baseline. ABI and TBI are taken in order to determine the existence and severity of peripheral arterial disease. ABI - The normal range for the ankle-brachial index is between 0.90 and 1.30. ABI <0.90 is abnormal: 0.41 to 0.90 indicates mild to moderate peripheral artery disease; 0.40 and lower indicates severe disease. The lower the index, the higher the chances of leg pain while exercising or limb-threatening low blood flow. TBI ≥ 0.7 is normal, TBI < 0.7 is abnormal.	baseline and week 16
Mean Change in Microvascular Blood Flow Composite Score	Measure of treatment effect using pulse volume recordings of the ankle, great toe and brachial artery to calculate the ankle brachial index and toe pressures composite score at week 16 from baseline. Composite score obtained by adding all the measurements and averaged. The score was tested by the Laser Doppler Flowmetry (LDF). Minimum score is 0 which mean no blood flow detected and there is no maximum value of the score, and higher score mean better blood flow.	baseline and week 16

Collaborators and Investigators

• Sponsor: Icahn School of Medicine at Mount Sinai
• Investigators: Principal Investigator: Robert Rosenson, MD, Icahn School of Medicine at Mount Sinai

Publications and helpful links

General Publications

• Rosenson RS, Chen Q, Najera SD, Krishnan P, Lee ML, Cho DJ. Ticagrelor improves blood viscosity-dependent microcirculatory flow in patients with lower extremity arterial disease: the Hema-kinesis clinical trial. Cardiovasc Diabetol. 2019 Jun 7;18(1):77. doi: 10.1186/s12933-019-0882-5.

Study record dates

Study Major Dates

• Study Start: April 1, 2015
• Primary Completion (Actual): May 4, 2018
• Study Completion (Actual): May 4, 2018

Study Registration Dates

• First Submitted: December 19, 2014
• First Submitted That Met QC Criteria: December 19, 2014
• First Posted (Estimate): December 25, 2014

Study Record Updates

• Last Update Posted (Actual): March 21, 2022
• Last Update Submitted That Met QC Criteria: March 18, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: Ticagrelor; Aspirin; Type 2 Diabetes; Peripheral Artery Disease; Blood Viscosity
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Endocrine System Diseases; Atherosclerosis; Peripheral Vascular Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Peripheral Arterial Disease; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Aspirin; Ticagrelor
• Other Study ID Numbers: GCO 13-1925

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No